Mitochondrial rewiring with small-molecule drug-free nanoassemblies unleashes anticancer immunity

Lulu Ren, Jianqin Wan, Xiaoyan Li, Jie Yao, Yan Ma, Fanchao Meng, Shusen Zheng (), Weidong Han () and Hangxiang Wang ()
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Lulu Ren: Zhejiang University School of Medicine
Jianqin Wan: Zhejiang University School of Medicine
Xiaoyan Li: Zhejiang University School of Medicine
Jie Yao: Zhejiang University School of Medicine
Yan Ma: Zhejiang University School of Medicine
Fanchao Meng: Zhejiang University School of Medicine
Shusen Zheng: Zhejiang University School of Medicine
Weidong Han: Zhejiang Cancer Hospital
Hangxiang Wang: Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.

Date: 2024
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DOI: 10.1038/s41467-024-51945-y

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